Over the past years, immune checkpoint inhibitors (ICIs) against cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1) or programmed death ligand 1 (PD-L1) have drastically changed the treatment landscape for patients with non-small cell lung cancer (NSCLC). Despite their success, a considerable proportion of patients will eventually consider ICI discontinuation due to disease progression, immune-related adverse events (irAEs) or the completion of a fixed duration course of ICIs without disease progression. Against this background, evidence is mounting that ICI retreatment could be an option for some patients. To date, however, no guidelines have been published for ICI rechallenge in lung cancer and it is still unclear which patients could benefit from a second course of ICI. In this, one needs to make a distinction between restarting the ICI without any other cancer treatment in between (retreatment) or restarting ICI after another treatment was used between the two ICI regimens (rechallenge). This is an important distinction as additional treatments may influence the homeostasis of the patients’ immune system.1,2 This article describes some of the key elements that could influence treatment outcomes upon ICI retreatment or rechallenge and addresses potential strategies for ICI rechallenge and safety management.